Ischemia occurs when blood flow to an area of cells is insufficient to support normal metabolic activity. If the condition persists for an extended period, the cells within the ischemic zone die. Reperfusion is the term used to describe the act of reestablishing blood flow to ischemic tissue. Hence, reperfusion is essential to the future survival of cells within an ischemic area. However, it is well known that reperfusion itself causes irreparable damage to many cells that survived the ischemic event. Therefore, compounds capable of minimizing and containing ischemic or reperfusion damage represent important therapeutic agents.
Reperfusion damage is largly the result of inflammatory processes. Reperfused ischemic tissue attracts leukocytes which release proteolytic enzymes and oxidants that in turn promote further inflammation followed by eventual healing and scarring. Since leukocyte-derived proteolytic enzymes and oxidants are non-selective, they degrade normal and reversibly injured tissue. Therefore, dampening the inflammatory response or inhibiting the most harmful agents in the inflammatory process are logical approaches for minimizing and containing reperfusion injury.
Evolving myocardial infarction is an ongoing process where the myocardium fails to receive adequate blood supply to support normal metabolic activity and is typically caused by coronary artery occlusion. Because of the constant, relatively high metabolic activity of the heart and the many therapies for alleviating coronary artery occlusion, evolving myocardial infarction is probably the most common, and serious setting for reperfusion injury.
Numerous therapeutic interventions, such as angioplasty, bypass surgery, and thrombolytic regimens, recannalize occluded coronary arteries and lead to myocardial reperfusion injury. See Lucchesi et al.; Leukocytes and Ischemia-induced Myocardial Injury, Ann. Rev. Pharmacol. Toxicol. 36: 159-163 (1985); and Engler, R. L.; Free Radical and Granulocyte-Mediated Injury during Myocardial Ischemia and Reperfusion, Am. J. Cardiol. 63: 19E-23E (1989).
Because recruited leukocytes have been implicated in extending myocardial infarction caused by coronary artery occlusion and reperfusion, neutrophil intervention is a logical approach for minimizing and containing evolving myocardial infarction. Such neutrophil interventions include neutropenia induction, anti-adhesion molecule monoclonal antibodies, and oxidant scavengers. See Romson et al.; Reduction of the Extent of Ischemic Myocardial Injury by Neutrophil Depletion in the Dog, Circulation 67: 1016-1023 (1983); Mullane et al.; Role of Leukocytes in Acute Myocardial Infarction in Anesthetized Dogs: Relationship to Myocardial Salvage by Antiinflammatory Drug, J. Pharmacol. Exp. Ther. 228: 510-522 (1984); Mitsos et al.; Protective Effects of N-2-Mercaptopropionyl Glycine against Myocardial Reperfusion Injury after Neutrophil Depletion in the Dog: Evidence for the Role of Intracellular-derived Free Radicals, Circulation 73: 1077-1086 (1986); Mitsos et al.; Canine Myocardial Reperfusion Injury: Protection by a Free Radical Scavenger, N-2-Mercaptopropionyl Glycine, J. Cardiovasc. Pharmacol. 8: 978-988 (1986); Jolly et al.; Canine Myocardial Reperfusion Injury: Its Reduction by the Combined Administration of Superoxide Dismutase and Catalase. Circ. Res. 54: 277-285 (1984); Simpson et al.; Reduction of Experimental Canine Myocardial Ischemia and Reperfusion Injury by a Monoclonal Antibody (Anti-Mol) that Inhibits Leukocyte Adhesion. Circulation 76: A0799, (1987); and Jolly et al.; Reduction of Myocardial Infarct Size by Neutrophil Depletion: Effect of Duration of Occlusion. Am. Heart J. 112: 682-690 (1986 ).
It has now been unexpectedly found that a group of compounds known to inhibit the action of several proteases are capable of containing and minimizing tissue damage caused by ischemia and reperfusion. The compounds are especially useful in a novel method for minimizing the detrimental effects to the heart caused during myocardial infarction and reperfusion.